tbuckley/cabot-search huggingface dataset:
A descriptive study on the treatment and outcomes of patients with platinum-sensitive, advanced, <i>BRCA-</i> or <i>PALB2-</i>related pancreatic cancer who have progressed on rucaparib.
Authors: Timothy J Brown, Mark H. O'Hara, Ursina R. Teitelbaum, Thomas Benjamin Karasic, Charles John Schneider, Natallia Izgur, Katherine L. Nathanson, Susan M. Domchek, Kim Anna Reiss
Journal: Journal of Clinical Oncology (2022)

4131 Background: We recently reported the results of a single arm phase II study of maintenance rucaparib in patients with platinum-sensitive advanced pancreatic cancer and a pathogenic variant in BRCA1, BRCA2, or PALB2 (NCT 03140670; Reiss, JCO 2021). However, optimal treatment following progression on PARP inhibitors (PARPi) has not been defined. Here, we report a descriptive study of post-progression treatment and outcomes of this patient population. Methods: Patients with advanced pancreatic cancer and germline or somatic BRCA1, BRCA2, or PALB2mutations treated with at least 16 weeks of platinum-based chemotherapy without progression were enrolled and treated with rucaparib until progression or unacceptable toxicity. At the time of progression, patients were treated with physician-choice chemotherapy. Here we evaluate the objective response rates (ORR) by RECIST 1.1. Overall survival (OS) and time to second progression (PFS2) calculated from trial enrollment and progression free survival on chemotherapy (PFS) by regimen were secondary endpoints. Time-to-event was analyzed by the Kaplan-Meier method and censored at date of last clinic visit, with a cutoff date of 12/10/21. Results: The trial enrolled 42 patients; 31 patients had progressed. Of these, 22 received second-line chemotherapy: nine were treated with an oxaliplatin-based regimen, nine were treated with a cisplatin-based regimen, and four were treated with non-platinum regimens. Demographics were balanced between those who received platinum versus non-platinum. All patients who received second-line chemotherapy regimens met the PFS2 endpoint and all but one patient had died at time of data cutoff. No patients had a complete response, five patients had a partial response (PR). By regimen, 1/9 patients treated with cisplatin had a PR, 3/9 treated with oxaliplatin had a PR, and 1/4 patients treated with non-platinum had a PR. OS, PFS2, PFS, and ORR results by regimen are shown in the table. Conclusions: In this small sample of patients with advanced pancreatic cancer with progressive disease on PARPi, chemotherapy retains some activity. Further study to identify predictors of response and/or resistance to post-PARPi treatment are underway. [Table: see text]
A novel, immunotherapy-based approach for the treatment of relapsed/refractory multiple myeloma (RRMM): Updated phase 1b results for daratumumab in combination with teclistamab (a BCMA x CD3 bispecific antibody).
Authors: Paula Rodríguez-Otero, Anita D'Souza, Donna Ellen Reece, Niels W.C.J. van de Donk, Ajai Chari, Amrita Y. Krishnan, Thomas G. Martin, Maria-Victoria Mateos, Daniel Morillo, David Duane Hurd, Laura Rosiñol, Anna Sureda Balari, Ralph Wäsch, Deeksha Vishwamitra, Shun Xin Wang Lin, Thomas Prior, Lien Vandenberk, Marie-Anne Damiette Smit, Albert Oriol Rocafiguera, Bhagirathbhai R. Dholaria
Journal: Journal of Clinical Oncology (2022)

8032 Background: Teclistamab (tec; JNJ-64007957) is a BCMA × CD3 T-cell redirecting bispecific antibody under investigation in patients (pts) with RRMM. Daratumumab (dara) is a CD38 mAb with direct on-tumor and immunomodulatory actions. Initial clinical data from the phase 1b multicohort TRIMM-2 study support the combination of tec + dara for the treatment of RRMM, with tolerable safety, no overlapping toxicities, and promising efficacy. We present updated results with additional pts and longer follow-up. Methods: Eligible MM pts aged ≥18 y had received ≥3 prior lines of therapy (LOT; including a proteosome inhibitor [PI] and immunomodulatory drug [IMiD]) or were double-refractory to a PI and IMiD. Pts treated with anti-CD38 therapy ≤90 d prior were excluded. Pts received dara SC 1800 mg per approved schedule and tec SC 1.5–3 mg/kg QW or Q2W. Primary objectives were to identify the recommended phase 2 dose of tec for combination therapy and evaluate safety of the combination. Responses were assessed by IMWG criteria. AEs were graded per CTCAE v5.0; cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) were graded per ASTCT guidelines. Results: At data cutoff (Jan 13, 2022; safety population: N=46), median follow-up was 7.2 mo (range 0.1–16.6; median age 67 y [range 50–79]; 52% female). Pts received a median of 6 prior LOT (range 2–17; 74% triple-class exposed; 63% penta-drug exposed; 15% anti-BCMA exposed). 91% of pts had ≥1 AE (grade 3/4 78%), most commonly CRS (61%; all grade 1/2; median time to onset 2 d; median duration 2 d), neutropenia (54%; grade 3/4 50%), anemia (46%; grade 3/4 28%), thrombocytopenia (33%; grade 3/4 28%), and diarrhea (33%; grade 3/4 2%). Infections occurred in 29 pts (63%; grade 3/4 28%). One pt had grade 1 ICANS that fully resolved. Among 37 response-evaluable pts, ORR was 78% (29/37); 27 pts (73%) had very good partial response (VGPR) or better (Table). Median time to first response across dosing cohorts was 1.0 mo (range 0.9–2.8); median duration of response was not reached. Upregulation of CD38 + /CD8 + T cells and proinflammatory cytokines was observed with tec + dara, supporting potential synergy of the combination in pts with prior anti-CD38 exposure. Updated results will be presented. Conclusions: Tec + dara provides a novel immunotherapy approach for the treatment of RRMM that may yield improved clinical efficacy in heavily pretreated pts. Clinical trial information: NCT04108195. [Table: see text]
Functional Diversity and Evolution of Bitter Taste Receptors in Egg-Laying Mammals
Authors: Akihiro Itoigawa, Takashi Hayakawa, Yang Zhou, Adrian D. Manning, Guojie Zhang, Frank Grutzner, Hiroo Imai
Journal: Molecular Biology and Evolution (2022)

Egg-laying mammals (monotremes) are a sister clade of therians (placental mammals and marsupials) and a key clade to understand mammalian evolution. They are classified into platypus and echidna, which exhibit distinct ecological features such as habitats and diet. Chemosensory genes, which encode sensory receptors for taste and smell, are believed to adapt to the individual habitats and diet of each mammal. In this study, we focused on the molecular evolution of bitter taste receptors (TAS2Rs) in monotremes. The sense of bitter taste is important to detect potentially harmful substances. We comprehensively surveyed agonists of all TAS2Rs in platypus (Ornithorhynchus anatinus) and short-beaked echidna (Tachyglossus aculeatus) and compared their functions with orthologous TAS2Rs of marsupial and placental mammals (i.e., therians). As results, the agonist screening revealed that the deorphanized monotreme receptors were functionally diversified. Platypus TAS2Rs had broader receptive ranges of agonists than those of echidna TAS2Rs. While platypus consumes a variety of aquatic invertebrates, echidna mainly consumes subterranean social insects (ants and termites) as well as other invertebrates. This result indicates that receptive ranges of TAS2Rs could be associated with feeding habits in monotremes. Furthermore, some orthologous receptors in monotremes and therians responded to β-glucosides, which are feeding deterrents in plants and insects. These results suggest that the ability to detect β-glucosides and other substances might be shared and ancestral among mammals.
Thulium fiber LASER (TFL) vs. Holmium LASER (HOL) for kidney stones in RIRS (Retrograde intrarenal Surgery): A randomised controlled trial
Authors: A. Singh, A.K.P Parikh, N.S. S, A.P Patil, R.B Batra, P.S Survase, A.G Ganpule, R.B.S Sabnis, M.R.D Desai
Journal: European Urology (2022)
In HF with mitral regurgitation, adding transcatheter mitral valve repair to medical therapy improved renal outcomes at 2 y
Authors: Kevin Damman, Harriette G.C. Van Spall
Journal: Annals of Internal Medicine (2022)

Source Citation Beohar N, Ailawadi G, Kotinkaduwa LN, et al. Impact of baseline renal dysfunction on cardiac outcomes and end-stage renal disease in heart failure patients with mitral regurgitation: the COAPT trial. Eur Heart J. 2022;43:1639-48. 35134897
Outcomes in patients with resected stage IIIA melanoma treated with adjuvant nivolumab or monitored with observation: A real-world study.
Authors: Anna C. Pavlick, Asim Amin, Justin C Moser, Tayla Poretta, Leon Alan Sakkal, Andriy Moshyk, Andrew J. Klink, Tammy Schuler, Bruce A. Feinberg
Journal: Journal of Clinical Oncology (2022)

e21534 Background: Nivolumab is approved in the United States and other countries as an adjuvant treatment for patients with completely resected stage III–IV melanoma based on results of the phase 3 CheckMate 238 trial, though the trial enrolled a limited number of patients with stage IIIA disease (AJCC-8). The objective of this real-world study is to describe characteristics, treatment patterns, and outcomes of patients with resected stage IIIA melanoma (AJCC-8) treated with adjuvant nivolumab or monitored with observation. Methods: In this retrospective, chart-review study, physicians from Cardinal Health’s proprietary Oncology Provider Extended Network (OPEN) extracted data from electronic health records of patients who had undergone complete surgical resection of stage IIIA melanoma between Jan. 1, 2018, and Dec. 31, 2019. Recurrence-free survival (RFS) and overall survival (OS) were evaluated from the date of resection and compared between the adjuvant nivolumab and observation cohorts using log-rank tests and adjusted Cox proportional hazards models (covariates included age, sex, race, region, payer type, ECOG PS, and Charlson Comorbidity Index). Discontinuations and deaths due to adjuvant nivolumab toxicity were assessed. Results: This study included 171 patients treated with adjuvant nivolumab and 38 patients monitored with observation. In the adjuvant nivolumab and observation cohorts, respectively, mean age was 57.4 and 68.1 years; most patients were male (59% and 68%) and white (90% and 87%); and median follow-up from resection was 20.7 and 25.0 months. Sentinel lymph node tumor burden of &lt; 1 mm was reported in 12% (n = 20) and 16% (n = 6) of patients in the adjuvant nivolumab and observation cohorts, respectively. The scheduled treatment course with adjuvant nivolumab was completed by 91% of patients (n = 155). RFS and OS rates were numerically higher with adjuvant nivolumab than with observation (Table). There was a trend toward RFS and OS benefit with adjuvant nivolumab versus observation (unadjusted RFS HR 0.53, 95% CI 0.26–1.09; adjusted RFS HR 0.62, 95% CI 0.28–1.40; unadjusted OS HR 0.55, 95% CI 0.19–1.57; adjusted OS HR 0.81, 95% CI 0.25–2.61). Discontinuation of adjuvant nivolumab due to toxicity occurred in 2% of patients (n = 4); no treatment-related deaths were reported. Conclusions: These real-world results confirm that patients with resected stage IIIA melanoma (AJCC-8) have a good prognosis. Treatment with adjuvant nivolumab may provide modest survival benefit over observation in this population, though increased sample size and additional follow-up are warranted.[Table: see text]
Code status discussions in outpatient setting.
Authors: Sonika Prasad, Nikita Jain, Nayha Tahir
Journal: Journal of Clinical Oncology (2022)

e13539 Background: In the face of the COVID 19 pandemic, goal-concordant care has been gaining further significance. Discussions about the care goals are best when they are exploratory, conversational, and longitudinal. Complex information processing is best done outside of a crisis. Ideally, these conversations should start with the primary care clinician who has a longitudinal clinical relationship with the patient. Methods: A quality initiative project was conducted at the Internal Medicine Residency Clinic located in Northwestern Medicine Woodstock Hospital. Review of order entry in electronic medical records and charts for code status was assessed for data gathering. Patients above the age of 65 years presenting for their annual physical visit were included in the study. Various interventions were done, including educating residents through didactic lectures, sending electronic reminders to the residents and formatting a template note including code status documentation. Pre and post-intervention data was gathered. Results: A total of 104 patients were in the pre-intervention group and 94 patients in the post-intervention group. Pre-intervention, code status was addressed in 33% of total patients interviewed during their annual physical visit. Post intervention, code status was addressed in 48% of the patients. Conclusions: This project was undertaken to increase awareness on a crucial aspect of the addressing code status in outpatient setting. Post intervention studies showed that addressing code status significantly increased. In order to fill the gap, we propose that addressing code status be a mandatory process or a reminder be generated in electronic health records.
The spatial landscape of clonal somatic mutations in benign and malignant prostate epithelia
Authors: A.M. Erickson, E. Berglund, M. He, M. Marklund, R. Mirzazadeh, N. Schultz, L. Bergenstråhle, L. Kvastad, A. Andersson, J. Bergenstråhle, L. Larsson, T. Rajakumar, K. Thrane, A.L. Ji, F. Tarish, A. Tanoglidi, J. Maaskola, R. Colling, T. Mirtti, F.C. Hamdy, D.J. Woodcock, T. Helleday, I.G. Mills, A. Lamb, J. Lundenberg
Journal: European Urology (2022)
Clinical response to tepotinib according to circulating tumor (ct) DNA biomarkers in patients with advanced NSCLC with high-level <i>MET</i> amplification (<i>MET</i>amp) detected by liquid biopsy (LBx).
Authors: Xiuning Le, Luis Paz-Ares, Jan Van Meerbeeck, Santiago Viteri Ramirez, Carlos Cabrera Galvez, David Vicente Baz, Young-Chul Kim, Jin-Hyoung Kang, Christopher Stroh, Dilafruz Juraeva, Rolf Bruns, Gordon Otto, Andreas Johne, Paul K. Paik
Journal: Journal of Clinical Oncology (2022)

9121 Background: Tepotinib, a potent, highly selective, oral, MET inhibitor, showed meaningful activity in patients (pts) with NSCLC with high-level METamp by LBx in VISION. Exploratory biomarker analyses are presented herein. Methods: Pts had 0–2 prior therapy lines, high-level METamp by LBx (Guardant360; MET copy number ≥2.5), and no MET exon 14 skipping or EGFR/ ALK alterations. Pts received tepotinib 500 mg once daily (450 mg active moiety). Primary endpoint was objective response by independent review; data cut-off: Aug 20, 2021. Exploratory biomarker analysis included LBx at baseline (BL), on treatment, and end of treatment (EOT). Early molecular response (eMR) was defined as undetectable METamp 6–8 weeks on treatment. Results: 24 pts were enrolled (median age: 63.4 years [yrs]; smokers: 88%; ECOG PS 1: 88%; adenocarcinoma: 67%). Treatment duration was ≥1 yr in five pts and ≥2 yrs in two pts (both ongoing). Overall, objective response rate (ORR) was 41.7% (95% CI: 22.1, 63.4). Treatment-naïve pts (n=7) had an ORR of 71.4% (29.0, 96.3), median (m) DOR was 14.3 months (2.8, not estimable [ne]), and mPFS was 15.6 months (1.4, ne). BL biomarker analyses according to clinical benefit (CR/PR/SD [n=11] vs PD/NE [n=13]) showed association with better outcomes in pts with focal METamp, or without MYCamp or RB1 mutation (Table). MYCamp/ RB1 mutation was detected in 4/7 pts with neuroendocrine/not otherwise specified histology; MYCamp in 2/3 pts with neuroendocrine histology. Low BL ctDNA mutant allele frequency (MAF) was associated with better outcomes. 14 pts had eMRs (ORR 71.4%); persistent METamp (n=4) was associated with lack of clinical response. 2/9 pts with EOT biomarker profiles had emerging resistance mechanisms (MET kinase domain mutations Y1230 and D1228); both had METamp re-emergence. Treatment-related adverse events included edema (composite term; any grade: 46%; Grade 3: 13%) and constipation (any grade: 17%; Grade ≥3: 0%). Conclusions: Tepotinib showed meaningful activity, especially in first line, in the first trial of a MET inhibitor in EGFR WT NSCLC with high-level METamp to enroll based on a convenient LBx assay. BL biomarker analyses indicated focal METamp, MYC/RB1 WT, and low ctDNA MAF were associated with improved outcomes. Serial LBx could monitor molecular response and evaluate resistance. Clinical trial information: NCT02864992. [Table: see text]
Defective mitophagy and the etiopathogenesis of Alzheimer’s disease
Authors: Kuan Zeng, Xuan Yu, Yacoubou Abdoul Razak Mahaman, Jian-Zhi Wang, Rong Liu, Yi Li, Xiaochuan Wang
Journal: Translational Neurodegeneration (2022)

Abstract Accumulation of impaired mitochondria and energy metabolism disorders are non-negligible features of both aging and age-related neurodegeneration, including Alzheimer’s disease (AD). A growing number of studies suggest that mitophagy disorders play an important role in AD occurrence and development. The interaction between mitophagy deficits and Aβ or Tau pathology may form a vicious cycle and cause neuronal damage and death. Elucidating the molecular mechanism of mitophagy and its role in AD may provide insights into the etiology and mechanisms of AD. Defective mitophagy is a potential target for AD prevention and treatment.
Historical early treatment effects of adjuvant endocrine therapy for breast cancer in high-risk subgroups: Reanalysis of BIG 1-98, SOFT and TEXT.
Authors: Meredith M. Regan, Samuel M. Niman, Gini F. Fleming, Barbara Walley, Giuseppe Viale, Beat J. K. Thurlimann, Sherene Loi, Marco Colleoni, Olivia Pagani, Prudence A. Francis
Journal: Journal of Clinical Oncology (2022)

508 Background: Clinical trials testing adjuvant endocrine therapy (ET) have not historically limited enrollment to patients with clinically high-risk breast cancer (BC), nor estimated treatment (trt) effects prior to 5 yrs. In light of recent trial results for adjuvant CDK4/6 inhibitors, we estimated early relative and absolute trt effects of aromatase inhibitor (AI) vs tamoxifen (T), with ovarian suppression (OFS) if premenopausal, in high risk subgroups. Methods: From pts enrolled in adjuvant phase 3 randomized clinical trials BIG 1-98 (postmenopausal, 5yr AI v T), TEXT (5yr AI+OFS v T+OFS) and SOFT (5yr AI+OFS v T+OFS v T), we identified subgroups with HR+/HER2- BC and high risk features (≥4 pLN; or 1-3 pLN with grade 3, pT≥5 cm and/or Ki-67≥20% [retrospectively centrally assessed]). TEXT randomized at start of adjuvant trt; BIG 1-98 and SOFT after chemotherapy. Disease-free survival (DFS) was defined from randomization to invasive recurrence at local, regional, distant or contralateral breast, second non-breast malignancy or death. We estimated trt effects as differences in 2, 3 and 5yr DFS Kaplan-Meier estimates (KM diffs at t yrs) and hazard ratios over time intervals of 0-2, 0-3 and 0-5 yrs (HRs over 0 to t yrs) to approximate the maturity of trial results with increasing follow-up. Results: The high-risk HR+/HER2- subgroups were 695/4922, 707/2660 and 526/3047 pts in BIG 1-98, TEXT and SOFT with 202, 122, 142 DFS events observed by 5 yrs since randomization. 60%, 46% and 44% of pts had ≥4 pLNs; 42%, 90% and 92% had chemotherapy. The table summarizes results. Conclusions: In re-analysis of clinical high risk HR+/HER2- subgroups of 3 trials each ̃700 pts, 5 yrs AI vs T had similar magnitude of early trt effects after 2-3 yrs follow-up of all pts vs trt effects observed after 27 mos median follow-up in monarchE trial (HR=0.70; KM diffs 2.7% at 2 yrs, 5.4% at 3 yrs; n=5637). Relative and absolute trt effects sometimes diminished when estimated over 5 yrs rather than over 2 yrs, but meaningful absolute differences remained at 5 yrs in contrast to Penelope-B trial results. Design and interpretation of high risk HR+/HER2- early BC trials may depend on timing of randomization and selection of backbone adjuvant trts; follow-up &gt;5 yrs must remain standard. [Table: see text]
MEDB-69. Clinical and molecular meta-analysis of three major medulloblastoma clinical trials (ACNS0331, SJMB03, ACNS0332) uncovers novel strategies to improve risk-stratified therapy
Authors: Kyle S Smith, Catherine A Billups, Sandeep K Dhanda, Laure Bihannic, Aksana Vasilyeva, Yimei Li, Jeff M Michalski, James M Olsen, Sarah Leary, Maryam Fouladi, Amar Gajjar, Arzu Onar, Paul A Northcott, Giles W Robinson
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Given the vast molecular heterogeneity present within medulloblastoma (MB) and considerable differences in therapy, we performed a meta-analysis of three large, recently published, prospective clinical trials (ACNS0331, SJMB03, ACNS0332) comprising 898 children with newly-diagnosed MB to shape future therapy. METHODS: Molecular subgroups, subtypes, and copy number variations were uniformly procured from DNA methylation profiles and mutations from next-generation sequencing. Patients were stratified into six clinically homogeneous groups for cross-trial comparisons: (1) ACNS0331_LDCSI - patients with non-metastatic (M0), non-residual (R0), non-anaplastic MB treated with low-dose (LD) craniospinal irradiation(CSI); (2) ACNS0331_SDCSI - patients with M0R0 non-anaplastic MB treated with standard-dose(SD) CSI; (3) SJMB03_SDCSI - patients with M0R0 non-anaplastic MB treated with SDCSI; (4) SJMB03_HDCSI - patients with metastatic (M+) MB treated with high-dose (HD) CSI; (5) ACNS0332_HDCSI - patients with M+ MB treated with HDCSI; (6) ACNS0332_HDCSI_Carbo - patients with M+ MB treated with HDCSI and carboplatin. RESULTS: 803 (WNT=125, SHH=122, G3=189, G4=367) of 898 patients formed the cohort. No significant difference was observed between the event-free survival (EFS) from ACNS0331_SDCSI and SJMB03_SDCSI or from SJMB03_HDCSI and ACNS0332_HDCSI when analyzed as a whole or by subgroup. ACNS0331_LDCSI outcome was inferior to the combined ACNS0331_SDCSI + SJMB03_SDCSI cohorts (p&amp;lt;0.001) and in G3 (p=0.030). ACNS0332_HDCSI_Carbo EFS was superior to ACNS0332_HDCSI + SJMB03_HDCSI only in G3/G4_subtype III (p=0.045). Additional molecular risk factor analysis identified M0R0 G3/G4_subtype VII and SHH without high-risk features as very low risk (&amp;gt;90% EFS) and M0R0 G3/G4_subtype III as high risk (&amp;lt;40% EFS). CONCLUSION: The comparable results observed across trials presents a welcome opportunity to reduce toxicity by eliminating excessive doses of chemotherapy (i.e. vincristine, cisplatin, and cyclophosphamide) from therapy. Furthermore, these results support molecularly driven risk classification as the means for a better, more-refined, treatment stratification.